We seek to advance knowledge of the mechanisms responsible for excessive collagen production by scleroderma fibroblasts. Scleroderma (Systemic Sclerosis;SSc) is a clinically heterogeneous and poorly understood disorder of the connective tissue that is characterized by vascular, immune/inflammatory and fibrotic manifestations. In spite of much effort, there are currently neither effective therapies nor reliable diagnostic/prognostic tools to manage the progression of tissue fibrosis, the main cause of morbidity and mortality in SSc. We base this application on exciting new evidence that circulating auto-antibodies against the PDGF receptor (PDGFR) are causally associated with the pro-fibrotic phenotype of SSc fibroblasts. Specifically, we have shown that anti-PDGFR auto-antibodies are only present in SSc sera, and that they can convert healthy fibroblasts into SSc-like cells. Identified markers of fibroblasts activation include excessive reactive oxygen species (ROS) production, Ha-Ras stabilization, increased PDGFR levels, and amplified collagen I transcription through TGF-2 independent activation of Smad3. We hypothesize a disease mechanism whereby anti-PDGFR auto-antibodies trigger a ROS-driven signaling cascade that promotes unopposed production of TGF-2, PDGFR, and collagen. Our model is in line with previous findings of elevated PDGFR in association with deregulated TGF-2 activity in SSc dermal lesions and explanted fibroblasts. It is also consistent with evidence of functional relationships between Ras and Smad signals, and reciprocally positive regulation of PDGF and TGF-2 signals. We propose to characterize key downstream events and pathogenic properties of the anti-PDGFR auto-antibodies. Whereas the former aim will be pursued using traditional cell culture systems, the latter one will employ a novel animal model of skin fibrosis. Completing these studies will improve our understanding of SSc pathogenesis, and may also identify novel therapeutic opportunities to manage tissue fibrosis more effectively. PUBLIC HEALTH RELEVANCE: Scleroderma is a relatively rare and often fatal disorder that affects mostly adult women. Death occurs from end-stage organ failure caused by massive fibrosis in the connective tissue of skin, vessels and internal organs. There are currently neither effective therapies nor reliable prognostic tools to manage disease progression, mostly due to our limited understanding of scleroderma pathogenesis. We have recently discovered that circulating auto-antibodies against PDGFR receptor (PDGFR) may represent a main determinant of the pro-fibrotic phenotype of scleroderma fibroblasts. The present application seeks to further characterize key mechanisms and pathogenic properties of anti-PDGFR auto-antibodies, with the long-term goal of developing new targeted therapies against this devastating disorder.